Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

Phosphorylation of MYC at Threonine-58 and Serine-62 regulates protein stability and transcriptional function. Using biochemical assays and super-resolution microscopy, Su and colleagues prove that unlike total or pT58MYC, pS62MYC specifically associates with the nuclear pore basket (NPB) and is distributed in a rim-like pattern surrounding the nuclear periphery. At the NPB, pS62MYC forms a complex with the histone acetyl transferase GCN5 to maintain a transcriptionally permissive chromatin landscape. pS62MYC localization to the nuclear pore and its interaction with GCN5 is mediated by PIN1, a master regulator of phosphorylation-directed MYC function.Expert Commentary: This work offers mechanistic insights into how specific phosphorylation events guide the nuclear localization and transcriptional function of MYC.Su Y, Pelz C, Huang T, Torkenczy K, Wang X, Cherry A, et al. Post-translational modification localizes MYC to the nuclear pore basket to regulate a subset of target genes involved in cellular responses to environmental signals. Genes Dev 2018;32:1398–1419.To discern the origins of abscopal responses (systemic responses with focal therapy) in lung cancer, Formenti and colleagues report on 29 patients treated with CTLA-4 blockage and radiation. Differences between responders and nonresponders included a lower absolute lymphocyte count, higher T-regulatory cells, and increased serum IFNβ. Strikingly, two T-cell clones were markedly expanded in a patient with a complete response. Both recognized a mutation in KPNA2, a gene induced by radiation. This suggests that the abscopal response is a result of immunogenic mutations exposed by radiation, their upregulation in the tumor, antigen cross-presentation, and T-cell activation inducing IFNβ.Expert Commentary: This study provides additional clues into the abscopal effect, furthering our understanding of this phenomenon and allowing for the potential to identify those patients who may benefit from this innovative strategy.Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E, Lhuillier C, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nature Medicine; Published online November 5, 2018; doi: 10.1038/s41591-018-0232-2.TBK1 and MEK are two downstream targets of KRAS signaling, and combined inhibition of these pathways can lead to synergistic antitumor responses in KRAS mutant tumors, although acquired resistance develops over time. Kitajimai and colleagues showed that induction of IGF1 and YAP1 signaling pathways was involved in the acquired resistance, driven by transcriptional reprograming associated with H3K27 promoter acetylation. This could be reversed by BET inhibition. Intermittent BET inhibitor treatment combined with MEK/TBK1 inhibition showed durable responses in mice without toxicity.Expert Commentary: These studies identify an effective combination treatment strategy for mutant KRAS tumors that are refractory to current treatment options. Careful drug scheduling can overcome toxicities associated with multiple drug combinations.Kitajima S, Asahina H, Chen T, Guo S, Quiceno LG, Cavanaugh JD, et al. Overcoming resistance to dual innate immune and MEK inhibition downstream of KRAS. Cancer Cell 2018;34:439–452.e6.Tumor allografts in mice lacking the autophagy regulator Atg7 exhibit reduced survival, suggesting that host autophagy promotes tumor growth. However, some tumor lines appear insensitive to loss of host autophagy. Poillet-Perez and colleagues show that loss of host autophagy decreases plasma levels of circulating arginine. Further, such mice exhibit increased serum levels of the arginine-degrading enzyme ARG1, which likely contributes to decreased levels of circulating arginine. They also showed that the tumor cell lines whose growth was affected by decreased host autophagy were arginine auxotrophs due to lack of argininosuccinate synthase 1. Consistent with their observations, increasing dietary arginine levels in Atg7-deleted mice partially restored both circulating arginine levels and the growth of tumor allografts.Expert Commentary: This work identifies a novel metabolic vulnerability of a subset of tumors, which could be taken advantage of therapeutically.Poillet-Perez L, Xie X, Zhan L, Yang Y, Sharp DW, Hu ZS, et al. Autophagy maintains tumor growth through circulating arginine. Nature 2018;563:569–73.Obesity-induced nonalcoholic fatty liver disease and subsequent progression to nonalcoholic steatohepatitis (NASH) are risk factors for hepatocellular carcinoma (HCC). Grohmann and colleagues challenge the dogma that NASH and fibrosis are required for obesity-induced HCC. Utilizing a mouse model of obesity and human liver samples from obese patients with or without NASH, the authors found that obesity-induced oxidative stress led to inactivation of the T-cell protein tyrosine phosphatase (TCPTP) and activation of STAT1 and STAT3. TCPTP was required for the development of NASH, fibrosis, and HCC. STAT1 and STAT3 had nonredundant functions. STAT3 was required for HCC but not for NASH, fibrosis, or T-cell recruitment.Expert Commentary: This study provides a mechanism to explain clinical observations that obesity-induced HCC can develop in the absence of cirrhosis.Grohmann M, Wiede F, Dodd GT, Gurzov EN, Ooi GJ, Butt T, et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 2018;1289–1306.3.e20.Tumor-infiltrating T regulatory cells (TITR) present a major barrier to cancer immune responses. Magnuson and colleagues generated a TITR transcriptional signature (∼100 genes). The TITR transcriptional signature was identical across different murine tumor types and conserved across human and murine tumors and tissues. Computational deconvolution of bulk gene expression data from The Cancer Genome Atlas uncovered correlates of their TITR signature across multiple types of human cancers. Finally, employing murine tumor models and CRISPR-mediated gene editing of Tregs, they validated that targeting TITR signature genes can selectively deplete Tregs in tumors.Expert Commentary: Across multiple murine tumors and human cancers, a conserved core transcriptional program can be identified that defines tumor-infiltrating Tregs.Magnuson AM, Kiner E, Ergun A, Park JS, Asinovski N, Ortiz-Lopez A, et al. Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types. Proc Natl Acad Sci U S A 2018;115:E10672–E10681.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.